Skeletal fractures due to low bone mass are projected to increase markedly as the United States population ages. Identifying and providing care to individuals at greatest risk for fracture is therefore of paramount importance. While the incidence of bone loss and fractures increases with aging, so too does the risk for developing a monoclonal gammopathy, a collection of plasma cell disorders which includes monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM). MGUS is the most common monoclonal gammopathy, affecting roughly 3.2% of adults aged 50 and older (correlating to nearly 3 million current US residents). While osteolytic lesions and fractures are a well-recognized complication of MM, far less is known about the skeletal health of subjects with MGUS and SMM. Recent data demonstrate that subjects with MGUS have an increased incidence of fractures. Our preliminary data demonstrate that MGUS subjects have significantly diminished bone mass, altered bone microstructure, and increased serum levels of factors [Dickkopf1 and macrophage inflammatory protein 1-1)] known to correlate with osteolytic lesions in MM. The objectives of this application are to characterize the bone changes that occur in humans with monoclonal gammopathies at both a skeletal level (through both epidemiologic and imaging-based approaches) and a cellular level (by determining if alterations in osteoblast (OB) and osteoclast (OC) activity across the entire spectrum of monoclonal gammopathies result from common mechanisms). Aim 1 seeks to examine bone microstructure (using high-resolution peripheral quantitative computed tomography) in patients with SMM and MM, and to determine if SMM is associated with an increased fracture incidence. Osteolytic lesions in MM bone disease result from both inhibition of OB progenitor cell differentiation and enhancement of OC lineage cell differentiation. Aim 2 seeks to determine the signaling pathways within OB and OC progenitor cells which are altered in MM, and whether these same alterations also occur in OB and OC lineage cells in MGUS and SMM. This will be determined by isolating highly-enriched OB and OC progenitor cell populations from the bone marrow of subjects with MGUS, SMM, or MM and matched controls, and determining changes in gene expression along both focused and potentially novel pathways. Aim 3 will focus on whether in vitro, OB and OC progenitor cell differentiation and activity can be modulated by selective inhibition of the signaling pathways identified in Aim 2 to prevent OB inhibition or OC stimulation induced by culture of OB and OC progenitor cells with BM plasma from MGUS, SMM, or MM subjects.